Human strokes are most often caused by thrombosis or thromboembolism. Abnormalities in coagulation and fibrinolysis are risk factors for ischemic stroke and brain infarction. Recent studies suggest a major role of cerebral vasculature in regulating antithrombotic, procoagulant and fibrinolytic pathways in brain. Generation of endogenous anticoagulant activated protein C (APC) is triggered by ischemia in preliminary studies. We have initially developed a mouse stroke model with fibrin-rich microvascular deposits and obstructions due to middle cerebral artery occlusion/reperfusion or thrombin-induced thromboembolism. Treatment with APC was protective in this thromboembolic model in wild type mice and in hypercoagulable mice lacking tissue plasminogen activator (tPA-/-). The in vitro anticoagulant activities of plasma protein S and APC are enhanced by high density lipoproteins (HDL). Our central hypothesis is that fibrolytic and anticoagulant mechanisms in brain and systemic circulation control the development of cerebrovascular thrombosis which has a major impact on functional and neuropathological outcome of focal cerebral ischemia. We hypothesize that therapeutic interventions with various natural anticoagulants (i.e., APC, protein S and HDL) or with combined anticoagulant and fibrinolytic (i.e., tPA) agents are protective and/or preventive in stroke. Wild type mice and hypercoagulable mice due to tPA(-/-) or uPA(-/-) or thrombomodulin (TM) functional homozygous knockout (TM/Pro) or protein C (+1-) heterozygosity will be subjected to stroke. Brain injury, local blood flow, neurologic outcome, deposition of fibrin, risk for hemorrhage and blood-brain barrier permeability will be studied. To test our hypothesis we propose to develop a mouse stroke model with definition of pathophysiological consequences of ischemic stroke in wild type mice and in various hypercoagulable mice (aim 1), and to determine the efficacy and safety of anticoagulant (APC, protein S and/or HDL) treatment (aim 2) and of tPA alone treatment and of combined treatment with APC, protein S and HDL (aim 3) after focal ischemic insult in wild type mice and in various hypercoagulable knockout mice. Proposed studies will define the role of hypercoagulable state in ischemic stroke and evaluate potential protective vs. deleterious effects of anticoagulant and fibrinolytic therapies for stroke.